HER2 Two

I met a charming patient in my office this week. A gentleman with advanced gastric cancer. Upon further examination of his cancer, the adenocarcinoma cells were found to be strongly positive for human epidermal growth factor receptor 2 (HER2).

Many of my readers are familiar with this surface receptor, a member of the epidermal growth factor family. It’s discovery, and the subsequent development of treatments directed toward this target, are well described in the literature. While most people are familiar with this protein in breast cancer, it is only in the last several years that we have recognized the importance of HER2 expression in diseases like gastric and esophageal cancer.

Discussing the implications with the patient and his sons, I realized that this attractive therapeutic target might not be available for use due to the patient’s underlying heart disease. One of the toxicities of HER2-targeted therapies is congestive heart failure. As I pondered the dilemma, I was reminded of one of my patients from 16 years earlier.

At that time, a strapping 69-year-old woman arrived in my office with a large, high-grade breast cancer and 13 positive lymph nodes. She was also HER2 positive. The problem was that in 1997, the drug trastuzumab was not widely available and never (not ever), used in the adjuvant setting. With that as a backdrop, I treated the patient based on laboratory analysis using the best combinations I could identify. Now, 16 years later, still free of disease, she represents a rare success for someone afflicted with such aggressive (and yes, HER2-positive) disease.

The reason this former patient came to mind was that her excellent success 16 years earlier had not required the use of HER2-directed therapy. Ingrid Ottesen had done very well using assay-directed therapy chemotherapy without the addition of trastuzumab.  All we needed for Ingrid was the best use of available drugs. Despite the possible contraindication for trastuzumab in this gentleman’s case, we can still hope for a good outcome if we use the available drugs that best meet his need. After all, it worked perfectly for Ingrid.

You can read about Ingrid in Chapter 14 in Outliving Cancer, to be released later this month.

Cancer and the Great Divide

There are two types of cancer patients: those we can treat and those we can’t. As I reflect on this year and the years past during which we have applied the process of laboratory-guided treatment, I am reminded of this fact.

The EVA-PCD functional profile enables us to choose active treatments for patients, but I have sometimes wondered whether we are, in fact, choosing patients for the available drugs.  While the end result may not be all that different, e.g. superior clinical outcomes over randomly administered (standard) therapies, the path to that outcome, leaves room for interesting discussion.

I first pondered this issue at the time of completion of our earliest study. That study was conducted in childhood acute lymphoblastic leukemia (ALL). Recognizing that the corticosteroids were among the most important drugs for ALL, we exposed freshly isolated lymphoblasts from ALL patients to dexamethasone (ex vivo). At the fourth day we measured the degree of cell death and separated the patients in “sensitive” and “resistant “ subgroups. Strikingly, those children whose lymphoblasts died in the laboratory following exposure to dexamethasone (ex-vivo), virtually all survived without relapse, while those children whose lymphoblasts did not die in the laboratory following dexamethasone exposure (ex-vivo) relapsed at an alarming rate with only 25 percent still alive at the sixth year of follow up (p=0.009).

What we had succeeded in doing by Day 4 of diagnosis was something that all the known prognostic factors, like age, WBC and male vs. female could not do, namely accurately identify the responders and survivors.

Today, when I test patients in our laboratory, I consistently double or even triple the response rates over standard protocols, yet a subset of patients are not found sensitive to the available therapies. Patients who do not respond to chemotherapy are today known, in the oncologic vernacular, as “failing therapy.” If we view these “non-responders” as a biologically distinct group (not unlike the dexamethasone-resistant ALL patients above) then our role, in the field of functional profiling, is to quickly segregate the responders (to available drugs) from the non-responders and move those “non-responders” immediately to something that will work for them. In this light, patients no longer “fail therapies” but instead “therapies fail patients.” It is then our mandate to use the ex-vivo platforms to find (and yes, discover) novel therapies and combinations that will meet their unmet need.

As the New Year is upon us I am filled with the expectation that 2013 will be one of discovery and innovation. Never before have so many interesting compounds been available for study. If we are fortunate enough to succeed in our efforts to collaborate with members of the drug development community and have the opportunity to intelligently apply functional profiling, for drug discovery, 2013 could be a very good year indeed.

Phar Lap and the Treatment of Leukemia

Phar Lap (1926-1932) was a thoroughbred horse bred in New Zealand. After winning the Melbourne Cup and 37 other races, his victory at the Agua Caliente racecourse in Tijuana, Mexico, established the track record in 1932.

With each victory, his detractors became more strident. He was even the target of an assassination attempt. To prevent him from winning (and thereby disrupting the betting odds) officials would add lead bricks to his saddle. On the occasion of the Melbourne cup of 1930 he carried 138 pounds of lead, yet won the race. A quote from the Sydney Morning Herald dated Wednesday, November 5, 1930, read, “The question was not which horse could win, but could Phar Lap carry the weight. Could he do what no other horse before him had done?”

It appeared that the one thing that race officialdom feared above all else, was a horse that could consistently beat the field and win the race.

The tale of Phar Lap was brought to mind after a colleague forwarded a paper published in the journal Leukemia on August 10, 2012: “The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry.” (E Matutes, AG Bosanquet et al, Leukemia, Letter to the Editor.)

Published as a letter to the editor, the paper describes correlations between the TRAC (tumor response to antineoplastic compounds) assay, a short-term suspension culture cell death laboratory assay (very similar to our work) and clinical response, time to progression and overall survival in patients with chronic lymphocytic leukemia (CLL) who received chemotherapy as part of the LRF CLL4 trial conducted in England between 1999 and 2004.

The initial trial was a blinded correlation between laboratory assay results and patient response to one of three treatment regimens. An examination of the data reveals a clear and statistically significant correlation between drug sensitivity and overall survival (p = .0001). The 10-year survival of drug sensitive patients was 28 percent, while the 10-year survival for drug resistant patients was 12 percent.

Significant correlations with survival were observed for known prognostic factors like 17p and 11q deletion, as well as IGHV mutational status. Correlations were also observed between the TRAC assay results and these prognostic factors.

The report goes on to describe a second randomization that took place at the time of disease progression, either failure of first-line therapy or reoccurrence within 12 months. In this part of the study, 84 relapsed patients were allocated to standard therapy and their outcomes were compared with 84 patients allocated to treatment guided by the TRAC assay. The drugs tested in the assay-directed arm included chlorambucil, cytoxan, methylprednisolone, prednisolone, vincristine, doxorubicin, mitoxantrone, 2CDA, fludarabine and pentostatin. In vitro resistance for combinations was defined as resistance to all constituent drugs in the combination, while drug sensitivity was defined as TRAC-assay sensitivity for any of the drugs used in combination. No discussion of synergy analysis was included.

In examining this study, I cannot help but be reminded of Phar Lap. First, marshaling a study of 777 CLL patients, and conducting 544 TRAC analyses, is a phenomenal undertaking for which these authors should be commended.

Second, the observation of a significant correlation between laboratory assay results and overall survival, as well as the biological implications of this platform’s capacity to correlate with molecular markers is a demonstrable and noteworthy success, however unheralded.

Where the analogy with poor Phar Lap’s struggles, weighted down with lead, becomes most poignant is the final portion of the study wherein 84 patients received assay-directed therapy. To wit, we must remember that in 2012, drug refractory CLL remains an incurable malignancy (with the exception of a small subset of successfully transplanted patients) and that no chemotherapy-alone trial has provided a survival advantage in this group. But this only begins to explain this trial’s results.

Among the virtually insurmountable hurdles that these investigators were forced to confront was the fact that fully 52 percent of the standard treatment arm group were destined to receive fludarabine. This drug, the current gold standard for previously treated patients who fail chlorambucil (constituting 73 percent of the patients in this part of the trial), has an objective response rate of 48 – 52 percent in this population. As the drug would likely be identified as active in vitro as well, this had the impact of pitting the assay arm and the standard arm against one another, frequently using exactly the same treatment.

While this does not mean that the assay arm could not succeed, it does have an enormous impact upon the sample size calculations used to determine the number of patients required to achieve significance.  No pharmaceutical company would ever allow a registration trial to be conducted against an “unknown” control arm, particularly one using the same therapy as the study arm – not ever! Despite these burdens, the assay-directed arm had a superior one-year survival, while virtually all other trends favored the group who received assay-selected therapy. The results of this study are worthy of recognition and further support the clinical relevance, predictive validity and importance of functional analyses. Yet, this interesting study in CLL is unceremoniously relegated to the status of a Letter to the Editor in Leukemia. Perhaps, like Phar Lap, no one really wants to upset the odds.

Systems Biology Comes of Age: Metastatic Lung Cancer in the Crosshairs

Cancer therapists have long sought mechanisms to match patients to available therapies. Current fashion revolves around DNA mutations, gene copy and rearrangements to select drugs. While every cancer patient may be as unique as their fingerprints, all of the fingerprints on file with the federal AFIS (automated fingerprint identification system) database don’t add up to a hill of genes (pun intended), if you can’t connect them to the criminal.

To continue the analogy, it doesn’t matter why the individual chose a life of crime, his upbringing, childhood traumas or personal tragedies. What matters is that you capture him in the flesh and incarcerate him (or her, to be politically correct).

The term we apply to the study of cancer, as a biological phenomenon is “systems biology.” This discipline strikes fear into the heart of molecular biologists, for it complicates their tidy algorithms and undermines the artificial linearity of their cancer pathways. We frequently allude to the catchphrase, genotype ≠ phenotype, yet it is the cancer phenotype that we must confront if we are to cure this disease.

Using a systems biology approach, we applied the ex-vivo analysis of programmed cell death (EVA-PCD®) to the study of previously untreated patients with non-small cell lung cancer. Tissue aggregates isolated from their surgical specimens were studied in their native state against drugs and signal transduction inhibitors. This methodology captures all of the interacting “systems,” as they respond to cytotoxic agents and growth factor withdrawal. The trial was powered to achieve a two-fold improvement in response.

At interim analysis, we had more than accomplished our goal. The results speak for themselves.

First: a two-fold improvement in clinical response – from the national average of 30 percent we achieved 64.5 percent (p – 0.00015).

Second: The median time to progression was improved from 6.4 to 8.5 months.

Third: And most importantly the median overall survival was improved from an average of 10 – 12 months to 21.3 months, a near doubling.

These results, from a prospective clinical trial in which previously untreated lung cancer patients were provided assay directed therapy, reflects the first real time application of systems biology to chemotherapeutics. The closest comparison for improved clinical outcome with chemotherapeutic drugs chosen from among all active agents by a molecular platform in a prospective clinical trial is . . .

Oh, that’s right there isn’t any.

Cancer Treatment – A Husband’s View

Guest blogger – Gary Brutsch

Dr. Nagourney is currently attending an international conference where he is an invited speaker. During his absence we will have guest bloggers sharing their views on chemosensitivity testing and the EVA-PCD® assay. Our first guest is Gary Brustch.

Five years ago, my wife of otherwise good health was diagnosed with Stage IV uterine cancer. Following a surgical “solution,” we commenced our search for the next best alternative to just waiting for the disease to take its course.

We settled on a protocol supervised by a major cancer treatment center in Texas. For a total of six months, my wife, Tina, was treated with a combination of chemotherapies. During this treatment we continued to look for medical care that was more scientific-based.

At the conclusion of their protocol, we were notified that the course of treatment had not been successful. At this time Tina’s cancer marker numbers were approaching 800. Two days after this notification we decided that our final option was to contact Robert Nagourney, MD, at Rational Therapeutics in Long Beach, CA.

Our decision was based on the belief that his tumor sensitivity based chemo architecture was probably a more effective method to treat her tumor growth.

After obtaining a tumor sample from Tina and subjecting it to a laboratory process (assay testing), Dr. Nagourney prescribed a specific chemotherapy cocktail for her treatment. After one month of supervised treatment, Tina’s cancer marker number was under one hundred.

We are now into our fourth year of maintenance supervised by Dr. Nagourney. Our united opinion seems to say that, as health challenged individuals we must demand that caregivers treat our health challenges on a focused, individual basis.

We cannot accept that one category of chemotherapy is good for all.

Scientifically-based Functional Profile Under Fire

Winston Churchill once said, “Democracy is the worst form of government, except for all the others that have been tried.” I am reminded of this quote by a “conversation” that recently took place on a cancer patient forum.

A patient wrote that they had requested that tissue be submitted for sensitivity analysis and their physician responded by describing this work as a scam. A scam is defined by the American Heritage Dictionary as slang for a “fraudulent business scheme.”

Continuing Churchill’s thread, we might respond, “that laboratory directed therapies are the worst form of cancer therapy, except for all the others that have been tried.”

Using functional profiling we measure the effect of drugs, radiation, growth factor withdrawal and signal transduction inhibition upon human tumors. Using our extensive database we compare the findings with the results of similar patients – by diagnosis and treatment status – to determine the most active and least toxic drug or combination for each patient.

The test isn’t perfect. Some patient’s cancer cells (about 5 – 7 percent of the time), do not survive the transport and processing, so no assay can be performed at all. Some patients are resistant to all available drugs and combinations. And finally, based on the established performance characteristics of the test, we can only double or in some circumstances triple, the likelihood of a clinical response.  This is all well documented in the peer-reviewed literature.

Despite this, it appears that in the eyes of some beholders these strikingly good results constitute a “scam.” So let us, in the spirit of fairness, and academic discourse examine their results.

First, it must be remembered that today in 2012 only a minority of cancer patients actually show objective response to available cancer therapies. Five-year survivals, the benchmark of success for advanced disease in oncology (those whose disease has spread beyond the primary site), have not changed in more than five decades.

The highly lauded clinical trial process, according to a study from the University of Florida, only provides a better outcome for a new drug over an old one, once for every seven clinical trials conducted

More disturbing, only one out of 14 clinical trials provide a survival advantage of 50 percent or greater for the successful treatment group.

According to a study from Tuft’s University, it takes 11 years and more than $1,000,000,000 dollars for a new drug to receive FDA approval.

And in a study published in the New England Journal of Medicine only 8 percent of drugs that complete Phase I (safe for human use) ever see the light of day for clinical therapy. This is the legacy of NCCN-guided, University-approved, ASCO-authorized clinical therapeutics programs to date.

As a practicing medical oncologist I am only too familiar with the failings of our modern clinical trial system. Having witnessed the good outcomes of our own patients on assay-directed protocols whose benefits derive from the intelligent use of objective laboratory data for the selection of chemotherapy drugs, I for one will NEVER return to business-as-usual oncology, regardless of what moniker the naysayers might choose to attach to this approach.

Chemosensitivity Testing – What It Is and What It Isn’t

Several weeks ago I was consulted by a young man regarding the management of his heavily pre-treated, widely metastatic rectal carcinoma. Upon review of his records, it was evident that under the care of both community and academic oncologists he had already received most of the active drugs for his diagnosis. Although his liver involvement could easily provide tissue for analysis, I discouraged his pursuit of an assay. Despite this, he and his wife continued to pursue the option.

As I sat across from the patient, with his complicated treatment history in hand, I was forced to admit that he looked the picture of health. Wearing a pork pie hat rakishly tilted over his forehead, I could see few outward signs of the disease that ravaged his body. After a lengthy give and take, I offered to submit his CT scans to our gastrointestinal surgeon for his opinion on the ease with which a biopsy could be obtained. I then dropped a note to the patient’s local oncologist, an accomplished physician who I respected and admired for his practicality and patient advocacy.

A week later, I received a call from the patient’s physician. Though cordial, he was puzzled by my willingness to pursue a biopsy on this heavily treated individual. I explained to him that I was actually not highly motivated to pursue this biopsy, but instead had responded to the patient’s urging me to consider the option. I agreed with the physician that the conventional therapy options were limited but noted that several available drugs might yet have a role in his management including signal transduction inhibitors.

I further explained that some patients develop a process of collateral sensitivity, whereby resistance to one class of drugs (platins, for example) can enhance the efficacy of other class of drugs (such as, antimetabolite) Furthermore, patients may fail a drug, then be treated with several other classes of agents, only then a year of two later, manifest sensitivity to the original drug.

Our conversation then took a surprising turn. First, he told me of his attendance at a dinner meeting, some 25 years earlier, where Dan Von Hoff, MD, had described his experiences with the clonogenic assay. He went on to tell me how that technique had been proven unsuccessful finding a very limited role in the elimination of “inactive” drugs with no capacity to identify “active “drugs. He finished by explaining that these shortcomings were the reason why our studies would be unlikely to provide useful information.

I found myself grasping for a handle on the moment. Here was a colleague, and collaborator, who had heard me speak on the topic a dozen times. I had personally intervened and identified active treatments for several of his patients, treatments that he would have never considered without me. He had invited me to speak at his medical center and spoke glowingly of my skills. And yet, he had no real understanding of what I do. It made me pause and wonder whether the patients and physicians with whom I interact on a daily basis understand the principles of our work. For clarity, in particular for those who may be new to my work, I provide a brief overview.

1.    Cancer patients are highly individual in their response to chemotherapies. This is why each patient must be tested to select the most effective drug regimen.

2.    Today we realize that cancer doesn’t grow too much it dies too little. This is why older growth-based assays didn’t work and why cell-death-based assays do.

3.    Cancer must be tested in their native state with the stromal, vascular and inflammatory elements intact. This is why we use microspheroids isolated directly from patients and do not grow or subculture our specimens.

4.    Predictions of response are not based on arbitrary drug concentrations but instead reflect the careful calibration of in vitro findings against patient outcomes – the all-important clinical database.

5.    We do not conduct drug resistance assays. We conduct drug sensitivity assays. These drug sensitivity assays have been shown statistically significantly to correlate with response, time to progression and survival.

6.    We do not conduct genomic analyses for there are no genomic platforms available today that are capable of reproducing the complexity, cross-talk, redundancy or promiscuity of human tumor biology.

7.    Tumors manifest plasticity that requires iterative studies. Large biopsies and sometimes multiple biopsies must be done to construct effective treatment programs.

8.    With chemotherapy, very often more is not better.

9.    New drugs are not always better drugs.

10.   And finally, cancer drugs do not know what diseases they were invented for.
While we could continue to enumerate the principles that guide our practice, one of the more important principles is humility. Medicine is a humbling experience and cancer medicine even more so. Patients often know more than their doctors give them credit for. Failing to incorporate a patient’s input, experience and wishes into the treatment programs that we design, limits our capacity to provide them the best outcome.

With regard to my colleague who seemed so utterly unfamiliar with these concepts, indeed for a large swath of the oncologic community as a whole, I am reminded of the saying “There’s none so blind as those who will not see.”

The Death of Christopher Hitchens

Among the more colorful writers, orators and pundits in the later part of the 20th Century and the early part of the 21st was Christopher Hitchens. Born in England in 1949, he moved to the United States where he became famous for his deeply held political views. An outspoken critic of injustice, he called it as he saw it. While his political leanings were mostly liberal, he was willing to take on the establishment on both sides of the political isle when he saw injustice and political hypocrisy.

Christopher Hitches died at age 62 from cancer of the esophagus. Although unapologetic for his use of alcoholic beverages and tobacco products, his lifestyle may have contributed to his diagnosis. What saddens me most is the possibility that he could have done better. And didn’t.

Like so many celebrities when they are diagnosed with cancer, Hitchens entered a realm that I call, “social medicine.” Not to be confused with socialized medicine and related political issues, social medicine is the process whereby the rich and famous receive care from the “right” doctors. These luminaries, through their channels and connections, are hand carried to the most famous physicians in the country. Their prominent and widely published ivory tower investigators then provide the best care money can buy. Yet, more often than not it is exactly the same therapy that they would have received from their home-town oncologists, who read the same journals, attend the same meetings and adhere to the same NCCN guidelines as the “best and the brightest” academics. We then conveniently chalk these patient’s failures up to the biology of the disease and the patient’s drug resistance rather than examining the more discomforting reality that protocol therapy doesn’t work for famous patients any better than it does is for anyone else.

But what if these patients just got the wrong treatment? What if the drugs these doctors chose were the very best for many, but not right for them? What if the right treatment was just right around the corner, but these prominent academics couldn’t see it? What if these patients had submitted a tumor sample for an EVA-PCD® assay and knew which drug or combinations would kill their cancer cells?

It isn’t that Christopher Hitchens or Steven Jobs are more important than any other patient. Their collective suffering and the losses to their families are no greater than any other cancer patient who confronts this illness. It’s just that they are famous and we know about it from the beginning to the end. We watch as these patients suffer through the toxicities and side effects of randomly administered therapies. And, in the case of Hitchens we are provided a blow-by-blow description in his writings. Unlike other patients who seek their care outside of the limelight, these celebrities are above the fray, protected by their handlers, PR agents and managers – they are unapproachable. With Jobs or Hitchens I would have relished the opportunity to offer any assistance possible, and through contacts at Apple I actually tried, but to no avail.

These individuals suffer and die in the public eye. Like salt in a wound, investigators like my colleagues and myself who are engaged in the pursuit of better, more intelligently delivered therapies, suffer with them. No, they are not more important, but it just seems so when you watch it every day on television, online, or in the print media, you clearly see an “in your face” example of a failing paradigm of cancer therapeutics.

Paradigm Shifts

Scientific dogma in all disciplines is slow to change.

I am again reminded of this by the recent publication of a book by Dava Sobel, “A More Perfect Heaven: How Copernicus Revolutionized the Cosmos” about the life and times of Nicolaus Copernicus. I use the term “dogma” intentionally, for Copernicus lived in the tumultuous times of the Protestant religious movement. Thus, his revolutionary concept of a heliocentric (sun-centered) solar system clashed with both scientific and religious dogmas.

Copernicus himself, a polymath, was a linguist, astronomer and a physician. His original observations in 1514 so conflicted with existing thinking regarding the geocentric solar system, that his treatise on the topic wasn’t published until 1543 – just a year before he died.

Copernicus, Galileo and Giordano Bruno — who himself was burned at the stake in 1600 for having the temerity to suggest that there might be other solar systems in the universe — were all victims of prevailing thinking that would not and could not yield to the burgeoning new understanding contained within Copernicus’s carefully constructed view of the cosmos.

These experiences are instructive, for they shine the light of day upon dogma in contemporary science and medicine. Failed attempts to utilize human tissue for the study of tumor biology led to an entire generation of cancer researchers to erroneously dismiss this profoundly important field of endeavor. No amount of data or cogent scientific argument could dissuade these authorities from their “dogmatic” position that human tissue could not predict cancer response. When one colleague in the field compiled all of the existing data and showed in an analysis that patients who received assay-sensitive drugs responded statistically, significantly more often than those who received assay-resistant drugs (p= 0.00000001) it had absolutely no impact on the “experts” opinions.

Perhaps today, 500 years later, we can learn something from Copernicus and his experience with scientific dogma.

English Patients Denied Access to Ipilimumab

Among the more interesting discoveries in recent years have been two breakthroughs in the management of malignant melanoma. One drug, vemurafenib, a tyrosine kinase inhibitor, acts specifically in patients who carry the BRAF (V600E) mutation. The second drug ipilimumab, offered commercially from Bristol-Meyers Squibb as Yervoy, is a monoclonal antibody that acts by blocking CTLA-4, thereby enhancing T-cell response to tumor antigens. While vemurafenib has a somewhat narrow target population, ipilimumab targets may extend to a broader range of melanoma patients and will likely find a role in other cancers.

The data supporting ipilimumab’s use in advanced melanoma was reported in a 2010 Phase III trial, which provided a superior median survival for those treated with the drug over those who received a placebo. Superior one and two-year survivals were also reported. Unfortunately, this did not rise to the level that met the standards of the English watchdog organization, National Institute for Health and Clinical Excellence (NICE). The chief executive of NICE did admit that the drug could “potentially be very effective for a small percentage of patients.” Unfortunately, under current NICE guidelines, that small percentage of patients will not have access to the drug.

This is not the first time that a drug, found effective for the treatment of a subpopulation of patients has been denied approval based upon cost efficacy and the comparatively limited population of patients who stand to gain.

The role of Avastin in breast cancer represents a similar dilemma for those patients who might benefit but cannot afford the out-of-pocket expenses. Indeed, NICE originally denied approval to bortezomib, a highly active drug for the treatment of multiple myeloma, based upon similar cost considerations.

What ipilimumab, Avastin and bortezomib have in common is that they are harbingers of the coming conflict between patients-in-need and society’s capacity to cover the increasing costs of cancer therapy. Cost efficacy questions will only be resolved when we have the capacity to identify likely responders prior to therapy, enabling us to use drugs only in those patients with the highest expectations of response. Marginal overall benefits that come at high price will continue to fail until we redouble our efforts to refine the process of drug selection for individual patients. Janet Woodcock, MD, from the FDA once said, that we need “a critical path” from bench to bedside to guide clinical decisions. The human tumor primary culture functional analyses that we employ can provide that critical path and we would hope limit the need for the broad-brush policy decisions that are being handed down by NICE and similar entities both here in the U.S. and abroad.